Vascular response patterns to targeted therapies in murine breast cancer models with divergent degrees of malignancy

Breast Cancer Research

Research

Cornelius Faber¹  Carsten Höltke¹  Walter Heindel¹  Max Masthoff¹  Emily Hoffmann¹  Anne Helfen¹  Bastian Maus¹  Lydia Wachsmuth¹  Christiane Geyer¹  Mirjam Gerwing¹  Tobias Krähling¹  Michel Eisenblätter²  Moritz Wildgruber³  Verena Hoerr⁴  Regina Schinner⁵  Uwe Hansen⁶  Katharina Kronenberg⁷  Uwe Karst⁷ 

[1] Clinic of Radiology, University of Münster, Münster, Germany;Clinic of Radiology, University of Münster, Münster, Germany;Department of Diagnostic and Interventional Radiology, Medical Faculty OWL, University of Bielefeld, Bielefeld, Germany;Clinic of Radiology, University of Münster, Münster, Germany;Department of Radiology, University Hospital, LMU Munich, Munich, Germany;Clinic of Radiology, University of Münster, Münster, Germany;Heart Center Bonn, Department of Internal Medicine II, University Hospital Bonn, Bonn, Germany;Department of Radiology, University Hospital, LMU Munich, Munich, Germany;Institute for Musculoskeletal Medicine, University of Münster, Münster, Germany;Institute of Inorganic and Analytical Chemistry, University of Münster, Münster, Germany;

关键词: Tumor vasculature;    Magnetic resonance imaging;    Targeted therapy;    Tumor microenvironment;    Immune checkpoint inhibition;    Sorafenib;   

DOI  :  10.1186/s13058-023-01658-9

 received in 2023-01-06, accepted in 2023-05-14,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundResponse assessment of targeted cancer therapies is becoming increasingly challenging, as it is not adequately assessable with conventional morphological and volumetric analyses of tumor lesions. The tumor microenvironment is particularly constituted by tumor vasculature which is altered by various targeted therapies. The aim of this study was to noninvasively assess changes in tumor perfusion and vessel permeability after targeted therapy in murine models of breast cancer with divergent degrees of malignancy.MethodsLow malignant 67NR or highly malignant 4T1 tumor-bearing mice were treated with either the multi-kinase inhibitor sorafenib or immune checkpoint inhibitors (ICI, combination of anti-PD1 and anti-CTLA4). Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) with i.v. injection of albumin-binding gadofosveset was conducted on a 9.4 T small animal MRI. Ex vivo validation of MRI results was achieved by transmission electron microscopy, immunohistochemistry and laser ablation-inductively coupled plasma-mass spectrometry.ResultsTherapy-induced changes in tumor vasculature differed between low and highly malignant tumors. Sorafenib treatment led to decreased tumor perfusion and endothelial permeability in low malignant 67NR tumors. In contrast, highly malignant 4T1 tumors demonstrated characteristics of a transient window of vascular normalization with an increase in tumor perfusion and permeability early after therapy initiation, followed by decreased perfusion and permeability parameters. In the low malignant 67NR model, ICI treatment also mediated vessel-stabilizing effects with decreased tumor perfusion and permeability, while ICI-treated 4T1 tumors exhibited increasing tumor perfusion with excessive vascular leakage.ConclusionDCE-MRI enables noninvasive assessment of early changes in tumor vasculature after targeted therapies, revealing different response patterns between tumors with divergent degrees of malignancy. DCE-derived tumor perfusion and permeability parameters may serve as vascular biomarkers that allow for repetitive examination of response to antiangiogenic treatment or immunotherapy.

【 授权许可】

CC BY   
© The Author(s) 2023

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